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2021 Game Changer Grant
Co-funded by SoSo Strong Pediatric Brain Tumor Foundation
Pratiti (Mimi) Bandopadhayay, Recipient
Dana Farber Cancer Institute
MYC activation in Diffuse Intrinsic Pontine Gliomas
In collaberation with Tim Phoenix at the University of Cincinnati.
Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brain tumor. With no advancements in treatment over the past 30+ years, there is a significant need to develop effective therapeutic. Recently, highly recurrent histone H3 K27M mutations have been identified as a critical initiating event in DIPGs. However, these mutations alone are insufficient to create DIPGs, and require cooperating genetic events to induce tumor formation. Compared to K27M mutations, which are present in upwards of 80% of all DIPGs, other genetic events are found at much lower rates, which presents challenges when trying to identify those that are important and those that are simply passengers. When analyzing DIPG tumors our group recently collected, we found a number of genetic alterations that while occurring in separate groups of tumor samples, all likely converged on the activation of a notorious oncogene called MYC. While only approximately 15% of DIPGs activate MYC using traditional methods, we find that with the addition of other non-traditional methods we have identified at least ‘doubles’ the number of tumors with MYC activation. Thus, although a well-known oncogene in other cancers, the importance of MYC activation may be underappreciated in DIPGs due to alternative and poorly characterized mechanisms of activation. Our data indicates that activation of the MYC signaling pathway likely plays an important role in DIPG formation by cooperating with H3K27M mutations.
In this study, we will validate that these new alterations converge on MYC activation, and define the mechanisms each alteration utilizes to promote the activation of MYC. In addition, we will conduct experiments to advance our understanding of how H3K27M mutations and MYC activation cooperate to promote DIPG formation and growth. The successful completion of the proposed studies will draw newfound attention to MYC activation as a key cooperating event in DIPG tumorigenesis, and identify key interactions and targets that may be shared or unique to specific MYC activating genetic events, which can be leveraged to develop new therapeutic strategies.